Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function
Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function
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DOI：
10.1038/emboj.2011.234
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发表时间：
2011-08-17
期刊：
影响因子：
11.4
通讯作者：
Rotin, Daniela
中科院分区：
文献类型：
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作者：
Persaud, Avinash;Alberts, Philipp;Rotin, Daniela
成纤维细胞生长因子受体 1 (FGFR1) 在动物发育和成年体内平衡过程中的细胞增殖和分化中发挥着关键作用。在这里，我们发现人类 Nedd4 (Nedd4-1) 是一种 E3 泛素连接酶，由一个 C2 结构域、4 个 WW 结构域和一个 Hect 结构域组成，调节 FGFR1 的内吞作用和信号传导。 Nedd4-1 主要通过其 WW3 结构域与 FGFR1 上的新型非规范序列（非 PY 基序）相互作用，直接结合并泛素化激活的 FGFR1。删除该识别基序 (FGFR1-Delta 6) 会消除 Nedd4-1 结合和受体泛素化，并损害激活受体的内吞作用，这在 Nedd4-1 敲低时也观察到。因此，FGFR1-Delta 6 或 Nedd4-1 敲低表现出持续的 FGF 依赖性受体 Tyr 磷酸化和下游信号传导（FRS2 α、Akt、Erk1/2 和 PLC γ 的激活）。 FGFR1-Delta 6 在人胚胎神经干细胞中的表达强烈促进 FGF2 依赖性神经元分化。此外，这种 FGFR1-Delta 6 突变体在斑马鱼胚胎中的表达会破坏前神经元模式（头部发育），这与过度的 FGFR1 信号传导一致。这些结果表明 Nedd4-1 是神经元分化和胚胎发育过程中 FGFR1 内吞作用和信号传导的关键调节因子。 EMBO 杂志 (2011) 30, 3259-3273。 doi：10.1038/emboj.2011.234； 2011 年 7 月 15 日在线发布
Fibroblast growth factor receptor 1 (FGFR1) has critical roles in cellular proliferation and differentiation during animal development and adult homeostasis. Here, we show that human Nedd4 (Nedd4-1), an E3 ubiquitin ligase comprised of a C2 domain, 4 WW domains, and a Hect domain, regulates endocytosis and signalling of FGFR1. Nedd4-1 binds directly to and ubiquitylates activated FGFR1, by interacting primarily via its WW3 domain with a novel non-canonical sequence (non-PY motif) on FGFR1. Deletion of this recognition motif (FGFR1-Delta 6) abolishes Nedd4-1 binding and receptor ubiquitylation, and impairs endocytosis of activated receptor, as also observed upon Nedd4-1 knockdown. Accordingly, FGFR1-Delta 6, or Nedd4-1 knockdown, exhibits sustained FGF-dependent receptor Tyr phosphorylation and downstream signalling (activation of FRS2 alpha, Akt, Erk1/2, and PLC gamma). Expression of FGFR1-Delta 6 in human embryonic neural stem cells strongly promotes FGF2-dependent neuronal differentiation. Furthermore, expression of this FGFR1-Delta 6 mutant in zebrafish embryos disrupts anterior neuronal patterning (head development), consistent with excessive FGFR1 signalling. These results identify Nedd4-1 as a key regulator of FGFR1 endocytosis and signalling during neuronal differentiation and embryonic development. The EMBO Journal (2011) 30, 3259-3273. doi:10.1038/emboj.2011.234; Published online 15 July 2011